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The "High" Ground of Marijuana

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Kyle McCurdy

on 22 September 2016

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Transcript of The "High" Ground of Marijuana

Breaking the Surface: The "High" Ground of Marijuana

By Kyle McCurdy

Overview
1. Background of current research state/predicaments
2. Multiple Sclerosis-what is it?
3. Fast acting example video
4. MS and the Endocannabinoid System
5. CB1/CB2 Agonist Therapy
6. Conclusion
Fast Acting Cure for a Similar Example
http://www.youtube.com/v/Z3IMfIQ_K6U?version=3&start=710&end=856&autoplay=0&hl=en_US&rel=0
MS and the Endocannabinoid System Research
Final Thoughts
The potential for endocannabinoid system/marijuana research is boundless. We have obvious remedies for symptoms in a myriad of conditions as well as likely cures in others. Any side effects, compared to many other life-demoting drugs, are healthfully nil.


The illegality of cannabis is outrageous, an impediment to full utilization of a drug which helps produce the serenity and insight, sensitivity and fellowship so desperately needed in this increasingly mad and dangerous world.
”-Carl Sagan

Multiple Sclerosis
"More importantly, modulating the activity of the endocannabinoid system turned out to hold therapeutic promise in a wide range of disparate diseases and pathological conditions, ranging from mood and anxiety disorders, movement disorders such as Parkinson’s and Huntington’s disease, neuropathic pain, multiple sclerosis and spinal cord injury, to cancer, atherosclerosis, myocardial infarction, stroke, hypertension, glaucoma, obesity/metabolic syndrome, and osteoporosis, to name just a few" (Pacher et al., 2006).

Significance
Current Problems with Research Ability
Total federal and state marijuana prisoners in 2004 = 44,816 (Mumola, 2004)
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Larger scheme: Nearly half (48.3%) of drug arrests in 2011 were for marijuana -- a total of 749,825. Of those, an estimated 658,231 arrests (42.4% of all drug arrests) were for marijuana possession alone.

1 marijuana arrest occurs every 42 seconds (Ferner, 2011).

"Prohibition has not only failed in its promises but actually created additional serious and disturbing social problems throughout society. There is not less drunkenness in the Republic but more. There is not less crime, but more. ... The cost of government is not smaller, but vastly greater. Respect for law has not increased, but diminished"-H.L. Mencken, renown and highly regarded journalist in 1925 (Branson, 2012).
Bottom Line: Gov. has a severe lock on cannabis

Since the 1970's when the war on drugs began, American taxpayers have spent more than 1 trillion dollars on it.

Speaking of money...plants are virtually free to grow. If the chemicals in marijuana even ameliorate half of the previously mentioned conditions, or even just one, the ability to grow your own pharmacy is astounding.

-Not very stimulating for the economy/no proprietary wealth can be extracted.

"Researchers however have discovered that some cannabinoids, including THC and cannabidiol (CBD) are able to promote the re-emergence of apoptosis so that some tumours will heed the signals, stop dividing, and die."

"Cannabinoids have been shown to have an anti-proliferative effect on different cancer cell lines."

etc., etc.
What is it?
-An autoimmune, demyelinating and neurodegenerative disease in which the initial cause is not completely known
- Epidemiological studies suggest that MS occurs in genetically susceptible populations exposed to some sort of environmental factor around puberty, most likely a viral infection. Triggers an immune response directed towards myelin self-peptides. Thus, autoimmune attack of myelinated neurons (Arevalo-Martin, 2012).
-Causes CNS inflammation and faulty neuronal conduction.

Symptoms
Early Symptoms of MS

Blurred or double vision
Thinking problems
Clumsiness or a lack of coordination
Loss of balance
Numbness
Tingling
Weakness in an arm or leg


Later Symptoms of MS

Unusual sensations and Pain (pins/needles, numbness, itching, burning, stabbing, tearing)
Bladder problems
Trouble walking
Muscle spasms/weakness
Dizziness
Fatigue
Sexual Trouble
Speech Problems
Introduction
Susceptible mice are infected with Theiler’s murine encephalomyelitis virus (TMEV) during pre-puberty causing experimental allergic encephalomyelitis (EAE).
-Model for MS, extremely synonymous in action.
-Labels myelin as an antigen, causing demyelination/neurodegeneration through inflammatory/immune responses.
-As neurons/other neural cells degrade and change environment, CNS inflammation increases and excitotoxicity stress occurs (through redistribution of ion channels/formation of compensatory never pathways) (Compston and Coles, 2002).

Myoclonus Diaphragmatic Flutter/"Belly Dancer's Syndrome"
CB1/CB2 receptor agonist WIN 55,212-2 severely inhibits DTH response to myelin peptides. After 10 days of WIN administration, mice had inhibited CNS inflammation for 25 days after termination of treatment. Lack of CB1/CB2 receptors did not display this result.

Virtually all EAE mice die and no recovery of the autoimmune disorder generally occurs. With treatment of WIN, significant long-lasting functional improvement occurs. Thus, cannabinoids have shown abolition of disease mechanisms.

(Arevalo-Martin et al., 2003)
Previous Research
Endocannabinoid system in CNS and all leukocytes expresses potent immunomodulatory effects (Galiegue et al., 1995). Found to inhibit Th1 inflammatory responses and promote Th2 responses (Klein et al, 1998).
TH1 inhibition caused MS symptom amelioration in animal models, CNS inflammation reduction, and even promoted remyelination (Arevalo-Martin et al., 2003).

CB1 deficient mice have shown rapid neurodegeneration, showing endocannabinoid system significance in neuroprotection during disease. Responds to homeostatic deviations (Pryce et al., 2003).

Impairment of the endocannabinoid system has been witnessed in MS patients and related to disease causing effects (Witting et al., 2006).
"A CB1/CB2 receptor agonist, WIN 55,212-2, exerts its therapeutic effect in a viral
autoimmune model of multiple sclerosis by restoring self-tolerance to myelin."
Angel Arevalo-Martin, Eduardo Molina-Holgado , Carmen Guaza (2012).
Previous Research Cont.
WIN
CBD
Materials/Methods
Mice infected with 10^6 plaque forming units of TMEV at 4 weeks age. EAE produced.
DTH responses measured directly after injection of 5ug PLP139-151 (myelin peptide) into alternate ears.
Ear thickness measured using digital precision micrometer. Measurement repeated 24 h after.
60 dpi DTH measured and mice split into 2 groups.
1 group (n=12) received injection of PBS with 5% BSA and .2% DMSO (the vehicle) each day.
Other group (n=24) received WIN 55,212-2 dissolved in same vehicle.
At 70 dpi, treatment ceased. PLP injection and DTH measured. WIN treated group split into 2 subgroups.
1 received no further manipulation, other injected once with 100 mg/kg cyclophosphamide (Cy), an alykylating agent currently used in some chemotherapy and various autoimmune disorders including MS. Works at the DNA level, suppresses immune system. Severe, life threatening side effects common, including various forms of cancer (i.e. bladder) and permanent infertility (Fairley et al., 1972).
At 110 dpi, experimental procedures performed (Rotarod and Activity Cage) .
Mice then anesthetized
Blood sample from heart collected. Brain, SC, spleen and cervical lymph nodes collected and cytokine analysis was performed. Splenocytes were isolated for further study.

Rotarod and activity cage tests used to evaluate neurological deficits.
Preformed at 60, 70, 77, 84, 91, and 110 dpi.
Isolated splenocytes used in adoptive transfer experiments.
10^8 splenocytes were transfered to mice infected with TMEV at 30 dpi. Six mice received vehicle only treated 110 dpi cells, another six received WIN-treated 110 dpi cells.
Animals monitored until 80 dpi, then DTH was measured and activity experiments were performed.

Materials/Methods Cont.
Results
WIN treated mice with EAE obtained long-term reduction in the autoimmune inflammatory response (Fig. 1).
Ear swelling was inhibited upon completion of treatment and persisted the length of experiment (70 dpi-110 dpi). Cyclophosphamide caused reversal of myelin self-tolerance.
Suggests that WIN/agonism of endocannabinoid system restores tolerance to self-antigens.


Results Cont.
WIN treated mice exhibited long-term functional improvement
Obvious effect 1 day after treatment (70 dpi) in both Rotarod (Fig. A) and Activity Cage experiments (Fig. B and C).
Effect was prevented over time with Cy present.

Results Cont.
WIN treatment increases percentage of CD4+CD25+Foxp3+ regulatory T cells (Treg) in CNS at 110 dpi.
Treg cells have been found to induce immune tolerance, regulating the autoimmune/inflammatory systems by controlling self reactive responses in many autoimmune disorders (Kohm et al., 2002, Sakaguchi et al., 2008).
A decrease in CD25+Foxp3- (activated T cells) also occured.
Importantly, Treg cells increased from 2% to 10% of total CD4 cells while activated T cells decreased from 50% to 20%.


Results Cont.
Splenocytes (white blood cells from spleen/splenic fluid) were transferred from the vehicle treated and WIN treated anesthetized 110 dpi mice to TMEV-infected mice at 30 dpi.
At 30 dpi, mice do not elicit an autoimmune inflammatory DTH response to PLP myelin peptide.
At 80 dpi, WIN treated splenocyte recipients exhibited significantly weaker DTH response and improved functional properties.
Collectively, WIN has been found to induce an active autoimmune-tolerance response that causes amelioration of pathogenic effects. Particularly here, WIN induces a peripheral, long lasting effect.

Conclusions
Long term decrease in CNS inflammation and increase in functional improvement in EAE stricken mice using CB1/CB2 agonist WIN.
Amelioration of EAE by THC in mice had been shown to be repealed in mice lacking CB2 receptors and long-term improvement was not witnessed (Maresz et al., 2007). Significance of CB2 peripheral receptors were not determined or how recovery occurred even after cannabinoid treatment.
In this study, self-antigen tolerance was shown to be necessary for desired remedy effects (portrayed by the Cy treatment suppressing immune tolerance and reactivating autoimmune response). Immuno-regulatory effect thought to occur at CB2 receptor, anti-inflammatory effect thought to occur at CB1 receptor.
Most studies have proposed neuroprotective ability of cannabinoids in the CNS only, whereas now we see immuno-modulation is heavily involved as well in the periphery.
WIN directly inhibits autoimmune inflammatory response to myelin peptide and indirectly through splenocytes.

Sources Cites
Arevalo-Martin, A., Molina-Holgado, E., Guaza, C (2012). A CB1/CB2 receptor agonist, WIN 55,212-2, exerts its therapeutic effect in a
viral autoimmune model of multiple sclerosis by restoring self-tolerance to myelin. Neuropharmacology. 63:385-393.
Arevalo-Martin, A., Vela, J.M., Molina-Holgado, E., Borrell, J., Guaza, C., 2003. Therapeutic action of cannabinoids in a murine model of
multiple sclerosis. J. Neurosci. 23, 2511- 2516
Branson, R (2012). War on drug a trillion-dollar failure. CNN.com. http://www.cnn.com/2012/12/06/opinion/branson-end-war-on
drugs/.
Fairley, K.F., Barrie, J.U., Johnson, W (1972). STERILITY AND TESTICULAR ATROPHY RELATED TO CYCLOPHOSPHAMIDE THERAPY.
Lancet. Vol 1:7750:568-580.
Ferner, M (2012). One Marijuana Arrest Occurs Every 42 Seconds in U.S.: FBI Report. Huffingtonpost.com.
http://www.huffingtonpost.com/2012/10/29/one-marijuana-arrest occu_n_2041236.html
Galiegue, S., Mary, S., Marchand, J., Dussossoy, D., Carriere, D., Carayon, S., Bouaboula, M., Shire, D., Le Fur, G., Casellas, P., (1995).
Expression of central and peripheral cannabinoid receptors in human immune tissues and leukocyte subpopulations. Eur. J. Biochem. 232, 54-61.
Gupta, S (2013). Weed. [Video Clip]. CNN. http://www.youtube.com/v/Z3IMfIQ_K6U?version=3&start=710&end=856&autoplay
&hl=en_US&rel=0
Hampson, A.J., Axelrod, J., Grimaldi, M. (2003). Generic Cannabinoids as antioxidants and
neuroprotectants http://www.google.com/patents/US6630507. Google Patents.
Klein, T.W., Newton, C., Friedman, H., 1998. Cannabinoid receptors and immunity. Immunol. Today 19, 373-381.
Kohm, A.P., Carpentier, P.A., Anger, H.A., Miller, S.D., 2002. CD4þCD25þ regulatory T cells suppress antigen-specific autoreactive immune
responses and central nervous system inflammation during active experimental autoimmune encephalomyelitis. J. Immunol. 169, 4712-4716.
Maresz, K., Pryce, G., Ponomarev, E.D., Marsicano, G., Croxford, J.L., Shriver, L.P., Ledent, C., Cheng, X., Carrier, E.J., Mann, M.K., Giovannoni,
G., Pertwee, R.G., Yamamura, T., Buckley, N.E., Hillard, C.J., Lutz, B., Baker, D., Dittel, B.N., 2007. Direct suppression of CNS autoimmune inflammation via the cannabinoid receptor CB1 on neurons and CB2 on autoreactive T cells. Nat. Med. 13, 492-497.
Pacher, P., Batkai, S. Kunos, G. (2006). The Endocannabinois System as an Emerging Target of
Pharmacotherapy. Phamaracological Reviews. 58:389-462.
Pryce, Gareth, et al. (2003). Cannabinoids inhibit neurodegeneration in models of multiple sclerosis. Brain. 126, 2191-2202.
Sakaguchi, S., Yamaguchi, T., Nomura, T., Ono, M., 2008. Regulatory T cells and immune tolerance. Cell 133, 775-787.
Witting, A., Chen, L., Cudaback, E., Straiker, A., Walter, L., Rickman, B., Möller, T., Brosnan, C., Stella, N., 2006. Experimental autoimmune
encephalomyelitis disrupts endocannabinoid-mediated neuroprotection. Proc. Natl. Acad. Sci. U S A 103, 6362- 6367.

Cy injection at 70 dpi
US Gov. Patent #1
US Gov. Patent #2
Full transcript